The difference between adherence to non- nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens was investigated. Better adherence was found in NNRTI-treated patients, especially when efavirenz was included in the regimen, compared with single PI-treated patients and in those with CD4 cell counts less than 200 × 106/l. By contrast, younger age, self-report of active drug use, fatigue or vomiting negatively affected adherence. Self-reported sexual dysfunction was significantly associated with non-adherence only in PI-treated individuals.
In HIV infection, adequate adherence to highly active antiretroviral therapy (HAART) is imperative to achieve and maintain virological and immunological success and to avoid the selection of drug resistance [1–5]. Nevertheless, there are several barriers to optimal adherence, including medication complexity [6–9]. Single protease inhibitor (PI)-based HAART is a difficult regimen to take because of multiple daily doses, the large number of pills, complicated dosing schedules, dietary instructions, an ability to incorporate treatment into daily routine, and adverse effects. In contrast, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART offers some advantages: high potency, good oral bioavailability, long half-life and the lack of food restrictions.
In order to compare HAART adherence between PI and NNRTI-treated patients, we conducted an inter-cohort analysis using the data from the Adherence Italian Cohort Naive Antiretrovirals (AdICONA) cohort , a multicentre study within the Italian Cohort of Antiretroviral-naive patients (ICONA)  and the Adherence Spallanzani (AdeSpall) cohort, a study conducted at the National Institute for Infectious Diseases ‘Lazzaro Spallanzani', IRCCS, Rome, Italy. The inclusion criterion was to be receiving HAART containing a single PI or NNRTI for at least one month. Exclusion criteria were: dementia of grade 2 or greater , or hospitalization at enrolment. A 16-item self-administered questionnaire  was used to collect data on adherence, interruption in drug supply, reasons for missing or discontinuing drugs, and HIV or HAART-related symptoms experienced during the past 4 weeks.
Non-adherence was defined as reporting to have missed at least one dose in the past week or to have ever experienced an interruption in drug supply. Ordinal independent variables such as reasons for missing or discontinuing drugs as well as self-reported symptoms were dichotomized to ‘not at all'/`a little’ versus ‘a fair amount'/`a lot’ and ‘absent'/`mild’ versus ‘moderate'/`severe', respectively. All variables found to be significantly associated with non-adherence in the univariate analysis were included in a multivariable logistic regression model. Interaction terms were included to test whether the association between each variable and the probability of being non-adherent was different in the two treatment groups.
A total of 596 individuals were included (348 from AdICoNA and 248 from AdeSpall): 72% were men, mean age 37 years (range 19–66); HIV was acquired through heterosexual intercourse in 36.4%, intravenous drug injection in 36.2%, men having sex with men in 23.8%; alcohol abuse was reported by 12.4% and active drug use by 7.8%. The median viral load was 1.90 log10 copies/ml (≤ 500 copies/ml in 71.4%) and the median CD4 cell count was 490 × 106 cells/l. The median time on antiretroviral therapy was 21 months (interquartile range; IQR 13–28) and on the last HAART scheme 11 months (IQR 5–18). Out of all participants, 42.6% were receiving their first HAART regimen. In 63.8% of individuals HAART included a single PI (179 indinavir; 117 nelfinavir; 61 saquinavir hard gel capsules; 23 ritonavir) and in 36.2% a NNRTI (116 nevirapine; 100 efavirenz).
A total of 274 participants (46.0%) reported non-adherence: 192 (50.5%) in the PI and 82 (37.9%) in the NNRTI-treated group [odds ratio (OR) 0.59; 95% confidence interval (CI) 0.42–0.84; P = 0.004]. Among patients receiving NNRTI, non-adherence was reported by 33 individuals (33.0%) treated with efavirenz and by 49 (42.2%) treated with nevirapine. Non-adherent patients were less likely to have a viral load of 500 copies/ml or less (OR 0.66; 95% CI 0.46–0.97; P = 0.03). Table 1 shows the variables associated with non-adherence. On multivariable logistic regression, better adherence was found in individuals receiving an efavirenz or a nevirapine-containing HAART regimen than in those treated with a PI-based scheme and in subjects who had a CD4 cell count less than 200 × 106 cells/l compared with those with a higher count. In addition, an age of 35 years or less, self-report of active drug use, fatigue, or vomiting, were associated with poorer adherence. The interaction term between sexual dysfunction and NNRTI use was significant (P = 0.004), indicating that the effect of sexual dysfunction on non-adherence was different in the two treatment groups. In particular, sexual dysfunction was associated with non-adherence in patients receiving PI-based HAART, but not in those receiving NNRTI-based HAART.
In contrast, there was no evidence that the association between the type of HAART and the risk of non-adherence was different in antiretroviral-naive or pre-treated patients (P value for interaction terms was respectively 0.08 for nevirapine and 0.78 for efavirenz compared with PI).
Our results show that NNRTI-containing regimens are associated with better adherence than single PI- containing regimens. Remarkably, the proportion of non-adherent patients was lower in individuals treated with efavirenz than in those receiving nevirapine. This is in agreement with another study , which found that, at months 4 and 8 of follow-up, patients who received NNRTI-containing regimens were significantly more likely to report 100% adherence than those who received PI-containing regimens. Moreover, in a randomized clinical trial , patients with undetectable viral loads in which a PI-based regimen was replaced with efavirenz-containing HAART (12%) reported to have missed doses less frequently than those who remained on PI (29%). Finally, treatment with efavirenz plus nucleoside reverse transcriptase inhibitors had a superior virological efficacy when compared with HAART with nucleoside reverse transcriptase inhibitors plus indinavir  or nevirapine [17–19]. These findings might be explained by differences in adherence patterns, toxicity profiles and intrinsic drug potency.
As far as self-reported symptoms are concerned, sexual dysfunction was associated with poorer HAART adherence in PI-treated but not in NNRTI-treated patients. Some studies reported that sexual dysfunction appeared to be a common side-effect of PI-containing HAART [20,21], but our study is the first to report its association with HAART non-adherence. This finding suggests that an accurate assessment of patient-reported symptoms, including sexual dysfunction, could be useful to optimize adherence by treating symptoms or choosing the most appropriate regimen.
Our study may have several limitations: first, treatment was not allocated randomly, raising the possibility of confounding by indication. Second, it may not be possible to generalize our findings to the entire HIV-positive population because our study included only regimens with a single PI.
In conclusion, the use of NNRTI-based HAART as a regimen-focused intervention strategy to optimize adherence should be considered in clinical practice. Nonetheless, in NNRTI-treated patients it remains crucial to assess and to try to prevent non-adherence, taking into consideration the low threshold of cross-resistance within this class of drugs.
1.Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al
. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med
2.Rodriguez-Rosado R, Jimenez-Nacher I, Soriano V, Anton P, Gonzalez-Lahoz J. Virological failure and adherence to antiretroviral therapy in HIV-infected patients. AIDS
3.Haubrich RH, Little SJ, Currier JS, Forthal DN, Kemper CA, Beall GN, et al
. The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group. AIDS
4.Bangsberg DR, Hecht FM, Charlebois ED, Zolopa AR, Holodniy M, Sheiner L, et al
. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS
5.Bangsberg DR, Perry S, Charlebois ED, Clark RA, Robertson M, Zolopa AR, Moss A. Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS
6.Stone VE, Hogan JW, Schuman P, Rompalo AM, Howard AA, Korkontzelou C, et al
. Antiretroviral regimen complexity, self-reported adherence, and HIV patients’ understanding of their regimens: survey of women in the HER study. J Acquir Immune Defic Syndr
7.Nieuwkerk PT, Sprangers MAG, Burger DM, Hoetelmans RM, Hugen PW, Danner SA, et al
. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. Arch Intern Med
8.Bartlett J, De Masi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS
9.Gifford AL, Bormann JE, Shivley MJ, Wright BC, Richmann DD, Bozzette SA. Predictors of self-reported adherence and plasma HIV concentrations in patients on multidrug antiretroviral regimens. J Acquir Immune Defic Syndr
10.Ammassari A, Murri R, Pezzotti P, Trotta MP, Ravasio L, De Longis P, et al
. Self-reported symptoms and mdications side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr
11.d'Arminio Monforte A, Cozzi Lepri A, Rezza G, Pezzotti P, Antinori A, Phillips AN, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS
12.Sidtis JJ, Price RW. Early HIV-1 infection and the AIDS dementia complex. Neurology
13.Murri R, Ammassari A, Gallicano K, De Luca A, Cingolani A, Jacobson D, et al
. Patient-reported non-adherence to HAART is related to protease inhibitor levels. J Acquir Immune Defic Syndr
14.Mannheimer S, Friedland G, Matts J, Child C, Chesney M. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clin Infect Dis
15.Becker S, Rachlis A, Gill J, Dejesus E, Pierone G, Kirkland L, et al
. Successful substitution of protease inhibitors with efavirenz (EFV) in patients with undetectable viral loads- prospective, randomized, multicenter, open-label study (DMP 049).
In: 8th Conference on Retroviruses and Opportunistic Infections
. Chicago, February 2001 [Abstract 20].
16.Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al
. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med
17.Phillips AN, Pradier C, Lazzarin A, Clotet B, Goebel F-D, Hermans P, et al
. Viral load of non-nucleoside reverse transcriptase inhibitor regimens for 2203 mainly antiretroviral- experienced patients. AIDS
18.Matthews GV, Sabin CA, Mandalia S, Lampe F, Phillips AN, Nelson MR, et al
. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naïve patients: a cohort study. AIDS
19.Cozzi-Lepri A, Phillips AN, d'Arminio Monforte A, Piersantelli N, Orani A, Petrosillo N, et al
. Virologic and immunologic response to regimen containiining nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naïve Antiretroviral (I.Co.N.A.) Study Group. J Infect Dis
20.Schrooten W, Colebunders R, Youle M, Molenberghs G, Dedes N, Koitz G, et al
. Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment. AIDS
21.Martinez E, Collazos J, Mayo J, Blanco M-S. Sexual dysfunction with protease inhibitor. Lancet
:810–811.#m AcknowledgementsThis research has been realized through the valuable contribution of all the AdICONA and AdeSpall Study Group members.For the AdICoNA Study Group: Aviano, Italy: U. Tirelli, G. Nasti; Brescia, Italy: G. Carosi, F. Castelli; Cagliari, Italy: P.E. Manconi, P. Piano; Chieti, Italy: E. Pizzigallo, M. Dalessandro; Firenze, Italy: F. Mazzotta, S. Lo Caputo; Latina, Italy: F. Soscia, L. Tacconi; Lucca, Italy: A. Scasso, A. Vincenti; Mantova, Italy: A. Scalzini, G.C. Fibbia; Milano, Italy: M. Moroni, A. d'Arminio Manforte (Scientific Committee), S. Melzi; Modena, Italy: R. Esposito, L. Cremonini; Napoli, Italy: M. Piazza, N. Abrescia, M.C. Izzo, M. De Marco, E. Manzillo, S. Nappa; Piacenza, Italy: F. Alberici, M. Sisti; Perugia, Italy: S. Pauluzzi, K. Loso, P. Mele; Roma, Italy: A. Ammassari (Scientific Committee), A. Antinori (Study Coordinator), G. Antonucci, M. Ciardi, S. Delia, P. De Longis, G. D'Offizi, G. Ippolito (Scientific Committee), M. Lichtner, R. Murri (Scientific Committee), L. Ortona, P. Narciso, P. Noto, N. Petrosillo, P. Pezzotti (Scientific Committee), G. Rezza (Scientific Committee), P. Santopadre, M.P. Trotta (Scientific Committee), V. Vullo, M. Zaccarelli; Torino, Italy: P. Caramello, G.C. Orofino; London, UK: A. Cozzi-Lepri (Scientific Committee); Baltimore, MD, USA: A.W. Wu (Scientific Committee). The authors would also like to thank M. Guarinieri and M.R. Iardino (ICONA Community Advisory Board) for their helpful suggestions.For the AdeSpall Study Group: A. Antinori (Study Coordinator), M.S. Aloisi, S. Bonfigli, M.C. Carvelli, P. De Longis, G.P. D'Offizi, G. Liuzzi, P. Narciso, P. Noto, V. Tozzi, M.P. Trotta, U. Visco Comandini, M. Zaccarelli. Special thanks go to the nursing staff of the Third Division of Infectious Diseases of the National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ (L. Bolzoni, O. Ceci, G. Cirnigliaro, A. Manfredi, C. Scalise) for their helpful contribution to the study.